DESCRIPTION (provided by investigator): Multiple B cell defects have been described in the NZB/WF1 model, but their specific role in lupus pathogenesis is unclear, beyond their role as autoantibody producers. One of the limiting factors has been the requirement of a complex genetic background, including the H-2z allele, which has restricted reagent availability and functional experiments. We have produced a new model of lupus with the 3 NZM2410-derived Sle genomic loci that are necessary and sufficient for disease induction on a B6 background. This triple congenic B6.TC strain is constituted by approximately 94% of B6 genome, but yet develops a fully penetrant lupus nephritis. B6.TC mice show the same B cell developmental defects as NZM2410, which include an accumulation of B1a cells in the peritoneal cavity and a splenic accumulation of plasma cells, due to an absence of responsiveness to CXCR12, which normally directs PC migration to the bone marrow. We propose to use the B6.TC model to characterize the genetics and the mechanisms of these two developmental B cell defects, and determine their role in lupus pathogenesis. In addition, we propose to breed a BCR Tg on B6.TC to compare the mechanisms of B cell tolerance in that strain to that of the FAS-deficient model. To accomplish this goal, we have three specific aims: 1. To characterize the mechanisms of PerC B1a accumulation in B6.TC mice, and to assess its role in pathogenesis. We hypothesize that B1a PerC accumulation in B6.TC mice results from intrinsic B1a cell defects and from an abnormal regulation from a non-B cell compartment. We predict that this regulation involves STAT4 signaling as STAT4 deficiency prevents PerC B1a accumulation in B6.TC. These hypotheses will be assessed, and the contribution of each Sle locus will be evaluated in the process. Finally, we will address the contribution of PerC B1a cells to autoAb production and clinical with mixed BM chimeras. 2. To determine the functional and genetic mechanisms leading to PC accumulation in B6.TC spleens. We hypothesize this defect results from intrinsic B cell defects during PC differentiation and non-B cell factors that create "survival niches" that support the maintenance of large number of long-lived PC in the spleen. We propose that these factors involve CD40L and IL-4, which are over-expressed by B6.TC T cells. Moreover, STAT6 deficiency restores normal B6.TC PC migration to the spleen. We propose to test these hypotheses and assess the contribution of each Sle locus in the process. 3. To determine the mechanisms responsible for the loss of B cell tolerance using the RF-specific AM14 H transgenic model. B6.TC mice spontaneously produce rheumatoid factor. We propose to use the AM14 H Tg that produce anti-IgG2aa RF to explore the mechanisms of loss of B cell tolerance in the B6.TC model, comparatively to the mechanisms described in the FAS deficient model. This B6.TC.AM14 will constitute a very valuable tool to track the fate and development of autoreactive B cells in a FAS intact autoimmune model.